Apparatus and method for enhanced intravascular phonophoresis including dissolution of intravascular blockage and concomitant inhibition of restenosis

ABSTRACT

Ultrasonic apparatus and method for coupling ultrasonic energy into intravascular walls to enhance phonophoresis and for dissolution of intravascular blockages. The apparatus includes a radiator for coupling ultrasonic waves and a piezoelectric crystal, connected with said radiator, for the intravascular generation of ultrasonic waves; said ultrasonic waves being propagated along a longitudinal axis of said piezoelectric crystal. A seed liquid is introduced proximate the radiator for promoting cavitation of intravascular fluid. In addition, enhancement of dissolution of intravascular blockages and inhibition of restenosis by chemical agents is significantly increased when combined with ultrasonic energy.

The present application is a continuation-in-part of pending U.S. patentapplication Ser. No. 07/945,275, filed Sep. 14, 1992.

BACKGROUND OF THE INVENTION

The present invention is generally related to phonophoresis and is moreparticularly directed to the intravascular generation of ultrasonicenergy for enhanced delivery of drugs and also for the dual purpose ofintravascular blockage removal and the prevention of restenosis.

It is known that ultrasound can transport a physiologically activeagent, or drug, across a membrane. Phonophoresis is defined as themigration of drug molecules, contained in coupling/contact agents,through the skin under the influence of ultrasound. It has beendemonstrated that ultrasound can drive a drug into skeletal muscle andparavertebral nerve, and an increase in percutaneous absorption ofseveral drugs by the influence of ultrasound has been reported by manyobservers. The usefulness of phonophoresis in chemotherapy is importantsince the ultrasound localizes drug delivery to a desired area, thusincreasing the effectiveness without increasing systemic toxicity.

Ultrasonic energy has been considered for removal of intravascularblockages due to both atherosclerotic plaque and intravascular bloodclots. It has been shown that ultrasonic energy is useful in fragmentingplaque and thrombosis, either as a result of mechanical action thereonor cavitation thereof, in which high energy ultrasound applied toliquids generates vapor-filled microbubbles, or "cavities," with theconcomitant rapid expansion and collapse of the cavities, accompanied bylocal intense hydraulic shock leading to fragmentation or dissolution ofthe thrombosis.

As set forth in co-pending application Ser. No. 07/625,919 filed Dec.10, 1990, a miniature ultrasonic ablation tool mounted at the tip of aflexible catheter and deployed in small diameter arteries is useful forremoval of intra arterial atherosclerotic plaque and/or blood clots.This reference is incorporated herewith, including all drawings andspecification, by this specific reference thereto.

While transluminal coronary angioplasty has gained wide acceptance,acute reocclusion after successful coronary angioplasty occurs inapproximately 5% of patients. Late restenosis (generally in less thanthree months) is a major clinical problem limiting the long-termefficacy of this treatment of atherosclerosis and occurs in 25% to 50%of patients.

The pathogenesis of restenosis is still not entirely clear, butangloscopic observations, autopsy specimens from patients undergoingcoronary angioplasty recently, and atherectomy samples from patientswith restenosis have demonstrated that the pathophysiologic processleading to acute occlusion after coronary angioplasty are mainly relatedeither to predominantly thrombotic mechanisms or major plaque dissectionwith intimal flaps and superimposed thrombosis, and that thepathophysiologic events leading to chronic restenosis involved vascularinjury, platelet deposition and thrombosis, organization andincorporation of thrombi and subsequent smooth muscle cell proliferationand connective tissue synthesis.

Because excessive platelet deposition at the site of coronaryangioplasty and finally smooth muscle cell proliferation appears centralto the process of restenosis, the use of an agent directed at thethrombus and smooth muscle cell has been considered. A number of agentshave been reported to inhibit smooth muscle cell proliferation,including heparin, immunosuppressants such as cyclosporin, fish oil andomega-3 fatty acid, calcium channel blockers, corticosteroids, captopriland other inhibitors.

The ultrasonic apparatus of the present invention is specifically usefulfor the enhanced phonophoresis and the dissolution of intravascularblockages with concomitant treatment for inhibition of restenosis.

SUMMARY OF THE INVENTION

In accordance with the present invention, ultrasonic apparatus generallyincludes radiator means for coupling ultrasonic waves into intravascularwalls and fluids, means connected with the radiator means for thegeneration of ultrasonic waves, and, importantly, separate means forpromoting cavitation of the intra-vascular fluid proximate the radiatormeans. This cavitation is important in the enhancement of phonophoresis.

More specifically, the radiator means may be sized for intravascularinsertion and the means for promoting cavitation includes lumen meansfor introducing a seed fluid into the intravascular fluid proximate theradiator means.

The seed fluid may comprise an aqueous saline solution containing carbondioxide with the carbon dioxide content in the solution being at mostabout 10 grams per weight per liter of solution. In addition, the seedfluid may include a separate composition having activity for theinhibition of restenosis, such as, for example, heparin. The apparatusof the present invention enhances the delivery of restenosis inhibitingdrugs into the vascular wall.

Further, means may be provided for storing the aqueous saline solutionat a pressure greater than atmospheric pressure. Also provided are meansfor transferring the pressurized aqueous solution into the lumen meansfrom an exterior container.

A valve for controlling the flow of the seed fluid into the lumen meansprovides a means for controlling the rate of clot dissolution.

Additionally, the apparatus may include amplified means, interconnectedbetween the radiator means and the piezoelectric crystal means, fortransmitting and amplifying mechanical vibration of an ultrasonicfrequency from the piezoelectric crystal to the radiator means.

More specifically, the amplifier means may comprise a cylindrical memberhaving two regions of different cross-sectional area, with a largercross-sectional region attached to the piezoelectric crystal, and asmaller cross-sectional region attached to the radiator.

In addition, the present invention, in combination, provides anultrasonic surgical apparatus which includes a catheter having at leastone lumen therethrough and adapted for intravascular positioning alongwith an ultrasonic transducer disposed in the catheter lumen at a distalend thereof. The ultrasonic transducer may include, as hereinbefore setforth, radiator means for coupling ultrasonic waves in clots,piezoelectric crystal means for generating ultrasonic waves, and meansfor promoting cavitation of the intravascular fluid proximate theradiator means.

In addition, a power source may be provided and disposed exterior to aproximate end of the catheter and electrically connected to theultrasonic transducer through the catheter lumen, causing thepiezoelectric crystal to generate ultrasonic waves.

Further specific enhancement of clot dissolution may be obtained throughthe use of active agents in combination with the ultrasonic transducer.

A method for dissolving intravascular clots in accordance with thepresent invention generally includes the steps of introducing ultrasonicwaves proximate intravascular blockages and promoting cavitation ofintravascular fluid proximate the intravascular blockages. Mechanicalviolence introduced by the cavitation is thereby effectively utilized toenhance the breakup of blockages such as clots.

More particularly, the step of introducing ultrasonic waves may includethe step of inserting a catheter having an ultrasonic transducer on oneend thereof into a vessel by positioning the ultrasonic transducerproximate a clot. The step of promoting cavitation includes theintroduction of seed fluid into the intravascular fluid proximate theclot with the seed fluid including an aqueous saline solution containingcarbon dioxide which preferably is maintained at a pressure greater thanabout 1 atmosphere before introduction into the intravascular fluid.

In addition, an active agent may be utilized in combination with theultrasonic transducer and/or means for promoting cavitation to promoteclot dissolution without damage to artery walls.

Further, a combination is provided for enhancing clot dissolutionactivity of a composition and/or inhibiting restenosis. In view of thepresent cost of such compositions and possible side effects thereof,this combination is a very important advance in the treatment ofintravascular blockages.

BRIEF DESCRIPTION OF THE DRAWINGS

A better understanding of the present invention may be had with theconsideration of the following detailed description, taken inconjunction with the accompanying drawings in which:

FIG. 1 is a diagram of ultrasonic surgical apparatus in accordance withthe present invention for clot ablation, generally showing a catheter,an ultrasonic transducer disposed within a catheter lumen, a powersource disposed exterior to a proximate end of the catheter andelectrically connected to the ultrasonic transducer through the catheterlumen, and a supply of pressurized seed solution for promotingcavitation in intravascular fluid;

FIG. 2 is an enlarged cross-sectional view of an ultrasonic apparatus inaccordance with the present invention;

FIGS. 3 and 4 are representations of the use of the apparatus in thepresent invention in clot dissolution; and

FIG. 5 is a representation of an alternative embodiment of the presentinvention.

DETAILED DESCRIPTION

Turning now to FIG. 1, there is shown ultrasonic surgical apparatus 10,generally including a catheter 12, an ultrasonic transducer 14, disposedat a distal end 16 of the catheter 12, and a power source 18 disposedexterior to a proximate end 20 of the catheter 12 and electricallyconnected to the ultrasonic transducer 14 for causing a piezoelectriccrystal 24 (see FIG. 2) to generate ultrasonic waves as hereinafterdescribed in greater detail. It should be appreciated that the catheter12 and power source 18 may be of any conventional design suitable foruse with the ultrasonic transducer 14, with the expected operatingfrequencies between about 50 kHz and 1.3 MHz, suitable for clotablation.

Also shown is a storage vessel 26 in fluid communication with thecatheter 12 and transducer 14 as will be hereinafter discussed ingreater detail.

It is well known in the art that low power ultrasonic resonators (i.e.,20 watt power consumption at resonance under load), such as are used forsurgical handpieces, must have all their parts manufactured to verytight tolerances in order to maintain capability of achieving highvibrational motion in air (i.e., unloaded). It is also well known thatthe addition of an undesigned mass or spring load to the tipsignificantly reduces the vibration amplitude at resonance, and thepower delivery capability. However, it has been found that resonatorsconstructed in accordance with the present invention, i.e., apiezoelectric crystal 24 having an entire end made from activepiezoelectric material, and having an inertial node within the body ofthe ceramic do not need metal pieces with accurate tolerances in orderto function. Furthermore, mass, spring, fluid, or point contact-typeloads applied to the radiator do not generally cause a loss of amplitudeat resonance but instead cause an increased power draw from the AC powersupply used to drive the crystal.

Turning now to FIG. 2, there is shown an enlarged view of the transducer14 of the present invention disposed at the distal end 16 of thecatheter 12.

A radiator 44 provides means for coupling ultrasonic waves into clots(see FIGS. 3 and 4) which includes a cylindrical body portion 46 and anarcuate radiating surface 48. It should be appreciated that while theradiating surface 48 is shown in the drawing with a generallyhemispherical shape, a number of blunt shapes may be utilized aseffective radiation of acoustic energy.

As hereinafter described in greater detail, this structure, in part,provides for more efficient radiation of ultrasonic energy in a forwarddirection than prior art radiators. An amplifier 58 may beinterconnected between the piezoelectric crystal 24 and the radiator 44for transmitting and amplifying mechanical vibration of an ultrasonicfrequency from the piezoelectric crystal 24 to the radiator 44.

The radiator 44 and the amplifier 58 may be formed from a single pieceof material, such as titanium. Titanium is a preferred material due toits lightweight nature and ability to vibrate longitudinally. Titaniumis further known to be relatively non-lossy to sound waves. In addition,it is chemically inert and its hardness resists cavitation erosion.These characteristics make it preferable as a material for the radiator44.

An opening 60 may be formed in the back face 62 of the amplifier 58 foraccepting the piezoelectric crystal 24, which typically would be squarein cross-section.

Extending outwardly from a junction 70 of the body portion 46 of theradiator 44 and the amplifier 58 is a circular flange having an "L"portion 74 thereon, which provides means for centering the transducer 14at the catheter distal end 16 within the catheter lumen 76 with the bodyportion 46 and radiating surface 48 extending outwardly therefrom.

In addition, a compliant support 78 may be provided adjacent to andsurrounding the piezoelectric crystal 24 for supporting and centeringthe piezoelectric crystal within the catheter lumen 76. The support 78may be formed of any suitable material which would adhere to an insidewall 80 of the catheter, or the catheter wall 82 may be formed with aberm 78 to accomplish the purpose of supporting the piezoelectriccrystal 24 in a centered coaxial relationship within the catheter lumen76.

Electrodes 88 and 90 may be disposed on opposite sides 92, 94 andinterconnected by way of electrical leads 100 to the power source 18 asshown in FIG. 1. The electrodes 88 and 90, as well as the power source18, may be of conventional design suitable for applying a voltagebetween the crystal faces 92, 94 in order to cause the mechanicalgeneration of ultrasonic waves, the latter being propagated along alongitudinal axis 104 of the piezoelectric crystal 24.

The piezoelectric crystal 24 may be of any suitable material well knownin the art having piezoelectric characteristics such as lead zirconatetitanate (PZT). Preferably the cross-section of the piezoelectriccrystal 24 is square with a diagonal dimension of about 1 mm to about 6mm, and for operating in a range of about 50 KHz to about 1.3 MHz, thelength, l, of the piezoelectric crystal 24 would be about 1.25 mm toabout 12.5 mm in order to sustain power output from the piezoelectriccrystal 24 sufficient to cause cavitation for disruption andliquefaction of blood clots.

While the dimensions of the radiator 44 and amplifier 48 are empiricallydetermined, in general the amplifier 44 length is greater than thepiezoelectric crystal 24 and amplifier 44 diameter is comparable to thecross-sectional dimensions of the piezoelectric crystal 24. The radiator44 diameter may be approximately equal to the piezoelectric crystal 24diagonal dimension.

The structure of the transducer 14 in accordance with the presentinvention promotes the forward projection of acoustic waves 110 alongthe longitudinal axis 104 as shown in FIGS. 3 and 4.

Referring again to FIG. 2, an outer lumen 120 in the catheter 12, whichsurrounds the interior lumen 76, provides a means for both promotingcavitation in intravascular fluid 122, proximate clots 126, and forintroducing a composition having clot dissolution activity as will behereinafter discussed. A representation of the cavitation is illustratedby bubbles 128 within the intravascular fluid 122, and a reduction inclot 126 is represented in FIG. 4.

The lumen 120 terminates in a cowling 130 surrounding the radiator 44exterior to the catheter 12.

A seed liquid at a pressure greater than 1 atm is provided by thestorage vessel 26 through a tube 134. A valve 136 provides a means forcontrolling the rate of clot dissolution through volume regulation ofthe seed fluid.

Cavitation occurs when the magnitude of the vacuum portion of thepressure-vacuum cycle in an acoustic wave within a liquid medium issufficiently high that dissolved gases in the fluid come out of solutionin the form of small observable bubbles 128. Typically the bubbleformation (and/or subsequent collapse during the following pressurecycle) has a characteristic random noise acoustic signature. It is alsoquite violent mechanically at the bubble site, a property that enhancesthe efficacy of the transducer 14 in clot dissolution.

The valve 136 is utilized to allow the passage of a small but steadyflow of cavitation seed liquid to the intravascular fluid 122.

The seed liquid is an aqueous saline solution impregnated with CO₂(carbon dioxide) in a concentration not exceeding 10 grams weight perliter of fluid. The seed liquid is kept in the vessel 26, sealed againstthe atmosphere until time of use, when it is carried through a lumen inthe catheter to the ablation/dissolution site. As the liquid exits itscontainer, its pressure drops to atmospheric pressure, and the CO₂begins to come out of solution in the form of small gas bubbles (seedbubbles). The concentration of CO₂ in the stored solution must beadjusted so that after transit through the lumen, the seed bubble 128size is still very small (less than 25 microns).

In the presence of the acoustic field of an ultrasonic transducer, thesmall seed bubbles become sites for cavitation in which they becomeenlarged, collapse, and/or are forced away from the face of thetransducer. The cavitation pressure threshold is lowered considerably,and the density of seed sites is very high--both conditions contributingto the occurrence of cavitation within a large volume of the acousticmedium in front of the transducer. (By contrast, naturally occurringcavitation appears to be confined to a region very close to the face ofthe transducer.) By adjusting the feed rate of the seed fluid, theresulting cutting/dissolution activity can be controlled for maximumeffect. A typical feed rate is 2 cc/min.

Experimental use of the hereinabove described transducer 14, with zeroseed fluid flow, has established that when the transducer is held withthe force of 60 grams against a submerged cross-sectional sample oftotally occluded artery preserved in formaldehyde and the piezoelectriccrystal 24 was driven with sufficient voltage at 100 KHz to produce avibrational amplitude of 6.2 microns (peak) at the radiator 44, steadypenetration of the radiator 44 into the clot was observed. The resultingcavity was a smooth-walled imprint of the radiator 44.

With regard to the dissolution of blood clots, a sample of approximately1 cubic centimeter in volume was removed from a large clot mass andsubmerged in a transparent plastic tray approximately 1 inch in diameterand 1/4 inch deep. The radiator 44 was placed in a permanent position ata depth of about 1/8 inch in the center of the clot and energized ashereinabove described. A portion of the clot within a 1/4 inch radius ofthe radiator 44 was dissolved in two to three seconds.

Continued driving of the piezoelectric crystal 24 produced violent fluidmotion and within one minute, the clot had separated into several pieceswith each being propelled in eddied currents around the tray and aimingof the transducer at each piece resulted in complete dissolution withinone additional minute. After a total lapsed time of about two to threeminutes, the appearance of the fluid in the tray was indistinguishablewith that of blood. In this experiment, the peak amplitude for clotdissolution was about 5 microns at 100 KHz; thus the voltage requirementis less for clot ablation.

These results are enhanced with seed liquid flow. In addition, it hasbeen observed that bubbles 128 of a certain size (25 to 50 microns) areentrained in the acoustic field of the transducer and projected withvery high speed (not yet measured, but much faster than the eye canfollow, perhaps 10 to 15 m/sec) through the intravascular fluid 122.Ultrasound propelled bubbles are postulated to produce sufficient shearforces along their path to separate red blood cells.

It is also expected that the transducer 14 will also exhibit dissolutionactivity at a distance from the working tip rather than strictly bydirect contact as has been the case for intravascular fluid 122transducers without cavitation enhancement.

It has been further found that the present invention exhibits a synergywith known compositions having clot dissolution activity. That is, theuse of ultrasonic energy with a composition having clot dissolutionactivity increases the dissolution rate up to two orders of magnitudeover the use of the composition alone. This is shown in the followingexample.

EXAMPLE

Two clot samples were prepared as follows:

Cored at 3 mm diameter from clot sample.

Washed in tap water, room temperature.

Weighed, placed at bottom of 1 ml vial with a 5 mm ID.

Covered with 1 ml streptokinase solution (strength: 2,500 units/ml,normal saline diluent).

Immediately following sample immersion, transducer OG-2 (3 mm×3 mm crosssection, 120 KHz operating frequency) was moved into contact with one ofthe clots. The transducer was then operated at a drive level of 75 vpeak with 50% duty cycle for a period of 90 seconds.

Temperature of the treated solution after ultrasound exposure was 40° C.

Results were as follows:

    ______________________________________                                                  Initial   Final                                                     Sample    Weight    Weight    Appearance                                      ______________________________________                                        CONTROL   .142 gm   .109 gm   Core sample intact                              U.S. + Strep                                                                            .120      .022      3 small pieces                                  ______________________________________                                    

The Example demonstrates the significant effect provided by thecombination of ultrasonic energy and composition having clot dissolutionactivity in actual clot dissolution. This synergism significantlyreduces the amount of composition necessary to effect clot dissolution.It can be easily appreciated that any side effects or unwanted activityof the compositions are consequently reduced because of the lower dosesnecessary to effect clot dissolution when used in combination withultrasonic energy.

The cavitation created by the apparatus 10 in accordance with thepresent invention is also useful in the enhancement of phonophoresis andis therefore useful in combination with any known drug, or active agent,and in treatment of conditions by phonophoresis. Such drugs include, butare not limited to:

    ______________________________________                                        Dexamethasone         Sodium chloride                                         Arabinosyl cytosine   Calcium chloride                                        BCNU                  Hydrocortisone                                          Cyclophosphamide's active                                                                           Tetracycline                                            metabolite            Streptomycin                                            Nitrogen mustard      Fluorafur                                               Melphalan             Physostigmine                                           Mannitol              Penicillin                                              Zinc oxide and tannic acid                                                                          Thiodine                                                Urea and dimethyl sulfoxide                                                                         Papain                                                  Lignocaine/lidocaine  Interferon                                              Lignocaine and dexamethasone                                                                        Penicillin                                              Benzydamine           Streptomycin                                            Fluocinolone acetonide                                                                              Tetracycline                                            Ibuprofen             Thiamin and                                             Benzoic acid          Ascorbic Acid                                           Potassium chloride                                                            ______________________________________                                    

Similar effects are expected with the use of drugs having activity toreduce restenosis. That is, the activity of a drug in reducingrestenosis is increased with ultrasonic energy by enhancement ofdelivery into a vascular wall.

The use of heparin to prevent acute occlusion and chronic restenosis isattractive because of its known antithrombotic effect and inhibitoryeffect on smooth muscle cell proliferation. Many mechanisms have beendescribed for heparin growth inhibition. The earliest mechanism proposedthat heparin, which is negatively charged, "scavenged" cationic growthfactors such as fibroblast growth factor and platelet-derived growthfactor. It has been shown that smooth muscle cells bind and internalizeheparin consistent with receptor-mediated endocytosis.

Unfortunately, doses used for systemic anticoagulant heparinization areaccompanied by the potent for hemorrhage, electrolyte shifts, andthrombocytopenia in the acute setting, and osteoporosis and alopeciaover longer periods of time. These disadvantages are overcome by theapparatus and method of the present invention utilizing ultrasound todelivery heparin, in which doses may be used which heretofore have beenless than conventionally used.

Turning now to FIG. 5, there is shown an alternative embodiment 150 ofthe present invention, suitable for clot dissolution in combination witha composition having clot dissolution activity as hereinabove described.

This embodiment 150 generally includes a piezoelectric crystal 152attached to a catheter 154 by means of an elastomeric material 156which, importantly, is affixed to the crystal 152, only at a midpoint160 thereof and surrounding a rear end 164 of the crystal 152 withoutattachment, or adherence thereto, which may leave an air gap 170 betweenthe elastomeric material 156 and the crystal 152.

In this configuration, with the rear end 164 of crystal 152 not beingloaded by the elastomeric material, sufficient ultrasonic waves may beintroduced into a vessel (not shown in FIG. 5) for the dissolution ofclots (not shown in FIG. 5).

As hereinbefore discussed, the piezoelectric crystal 152 may be poweredby a set of electrical leads 174 interconnected to the power source 18,shown in FIG. 1. An auxiliary lumen 180 is provided in the catheter 154to provide means for introducing a composition having clot dissolutionactivity proximate the crystal 152 within the vessel. The crystal 152provides a means for intravascular generation of ultrasonic waves withinthe vessel, in combination with a composition having clot dissolutionactivity, as hereinabove discussed, and provides a combination forintravascular clot dissolution and apparatus for enhancing clotdissolution activity of a composition.

Although there has been hereinabove described a specific arrangement ofultrasonic surgical apparatus and a method for dissolving intravascularblockage and inhibiting restenosis in accordance with the presentinvention, for the purpose of illustrating the manner in which theinvention may be used to advantage, it will be appreciated that theinvention is not limited thereto. Accordingly, any and allmodifications, variations, or equivalent arrangement which may occur tothose skilled in the art should be considered to be within the scope ofthe invention as defined in the appended claims.

What is claimed is:
 1. Ultrasonic apparatus comprising:radiator meansfor directing ultrasonic waves into intravascular walls and fluid, saidradiation means being sized for intravascular insertion; means,connected with said radiator means, for the generation of ultrasonicwaves; and separate means for both promoting cavitation of theintravascular fluid proximate the radiator means and for introducing aphysiologically active agent proximate the radiator means.
 2. Theapparatus according to claim 1 wherein the means for promotingcavitation and introducing a physiological active agent comprises lumenmeans for introducing a seed fluid into the intravascular fluidproximate the radiator means.
 3. The apparatus according to claim 1further comprising a seed fluid and the means for promoting cavitationand introducing the physiologically active agent comprises lumen meansfor introducing the seed fluid into the intravascular fluid proximatethe radiator means.
 4. The apparatus according to claim 3 wherein theseed fluid comprises an aqueous saline solution containing carbondioxide and a physiologically active agent.
 5. The apparatus accordingto claim 1 wherein the physiologically active agent comprises heparin.6. The apparatus according to claim 1 wherein the physiologically activeagent comprises a composition having activity for inhibiting restenosis.7. The apparatus according to claim 1 wherein the physiologically activeagent comprises a composition having clot dissolution activity and acomposition having activity for inhibiting restenosis.
 8. The apparatusaccording to claim 7 wherein the composition having clot dissolutionactivity comprises streptokinase and the composition having activity forinhibiting restenosis comprises heparin.
 9. A method for couplingultrasound into intravascular walls and fluid, said method comprisingthe steps of:introducing ultrasonic waves proximate intravascular wallsand fluid comprising inserting a catheter, having an ultrasonictransducer on one end thereof, into a vessel and positioning theultrasonic transducer proximate a selected intravascular wall; providingmeans for promoting cavitation of intravascular fluid proximate theintravascular walls; and introducing into the intravascular fluid acomposition, having physiological activity, proximate the intravascularwall.
 10. The method according to claim 9 wherein the step of promotingcavitation comprises introducing a seed fluid into the intravascularfluid proximate the intravascular wall.
 11. The method according toclaim 9 wherein the step of promoting cavitation comprises introducingan aqueous saline solution, containing carbon dioxide, into theintravascular fluid, proximate the intravascular wall.
 12. A method fordissolving intravascular blockages and inhibiting restenosis, saidmethod comprising the steps of:introducing ultrasonic waves proximate anintravascular blockage comprising inserting a catheter, having anultrasonic transducer on one end thereof, into a vessel and positioningthe ultrasonic transducer proximate the intravascular blockage;providing means for promoting cavitation of intravascular fluidproximate the intravascular blockage; and introducing a compositionhaving restenosis-inhibiting activity proximate the intravascularblockage.
 13. The method according to claim 12 wherein the step ofpromoting cavitation comprises introducing a seed fluid into theintravascular fluid proximate the blockage.
 14. The method according toclaim 12 wherein the step of promoting cavitation comprises introducingan aqueous saline solution, containing carbon dioxide, into theintravascular fluid, proximate the blockage.
 15. The method according toclaim 12 wherein the step of promoting cavitation comprises introducingan aqueous saline solution, at a pressure greater than about 1atmosphere, into the intravascular fluid proximate the blockages.